Stroke is the leading cause of adult disability. As the population ages, stroke incidence is expected to markedly increase, fostering an intense research focus on mechanisms of repair and recovery in this disease. However, this research focus has been directed almost entirely to experimental models of large artery or cortical infarcts. These models produce strokes in cortex, striatum or both. However, up to 25% of all strokes in humans occur in white matter. White matter strokes are a source of significant disability and can accumulate to cause vascular dementia, the second leading cause of dementia. Studies in white matter injury in models of multiple sclerosis indicate that glial progenitor cells can respond to the injury and initiate a process of repair and even recovery. There have been no studies of the possibility of white matter repair and recovery in subcortical or white matter stroke. This limitation has been due to lack of an effective animal model of white matter stroke. We have recently developed a model of subcortical stroke in white matter below the mouse forelimb motor cortex that models many aspects of this disease in humans. This mouse model indicates that white matter stroke produces a zone of complete damage and death of oligodendrocytes, but also a surround of evolving partial damage, an expansion of oligodendrocyte progenitor cells, and new populations of oligodendrocytes. This process in the stroke surround suggests a partial white matter repair in stroke. The goals of this grant are to determine the cellular and molecular mechanisms of white matter repair in subcortical/white matter stroke, to extend these findings to aged animals, and to manipulate these systems to enhance white matter repair and functional recovery. The proposed studies will use a multi-disciplinary approach of genetic cell fate mapping, electrophysiological characterization of white matter function, behavioral study of mouse motor recovery and laser capture and genetic analysis of glial progenitor responses in white matter stroke. These studies will take a field of stroke in which there is no data on white matter repair, develop a detailed cellular and molecular understanding of glial progenitor responses and white matter repair, and then manipulate candidate molecular systems to determine their causal role in repair and recovery in this disease. PUBLIC HEALTH RELEVANCE: Stroke in the areas of the brain that carry connections, termed cerebral white matter, is a common subtype of stroke. However, there have been few studies of the mechanisms of damage and brain repair in this disease. The studies in this grant determine the molecular and cellular mechanisms of repair and recovery in white matter stroke.